ABSTRACT The overall goal of the Sidney Kimmel Comprehensive Cancer Center (SKCCC) Cancer Chemical and Structural Biology (CCSB) Program is to: 1) discover, validate and characterize novel molecular targets for developing new therapeutic agents against human cancers; 2) identify new small molecules with anticancer potential and optimize their potency; and 3) improve the delivery of existing and promising new therapeutic agents. To accomplish these goals, the Program comprises faculty members across the university (e.g., the medical school, the Whiting School of Engineering and Homewood). CCSB fosters major interactions among SKCCC members and includes 22 Program members from nearly a dozen departments. Eighteen members have peer-reviewed support, with NCI and other peer-reviewed support of Program members totaling more than $10.7 million total costs and all Program support totaling $11.6 million. The productivity of CCSB members is demonstrated by the 611 publications, of which 43 (7%) were Intra-Programmatic, 144 (24%) were Inter- Programmatic and 202 (33%) were multi-institutional collaborations. Activities for the next project period stand to focus on three complementary aims: Aim 1: Characterize both new and existing targets using biophysical and chemical approaches. Aim 2: Develop small-molecule screening methods and optimize novel lead compounds for cancer targets. Aim 3: Develop methods for assessing and optimizing the delivery of anticancer drugs. The first goal describes predominantly laboratory-based efforts, with a focus on identifying and validating preclinical targets, and on ?proof of principle? experiments needed for further clinical testing. These activities include molecular, structural and cell biology studies, coupled with cellular and whole-animal assays, and preclinical pharmacokinetic and dynamic analyses. The second goal involves developing new chemical libraries and carrying out small-molecule screening and optimization against CCSB targets. The third goal centers on developing new methods for small-molecule delivery, including pro-drugs, encapsulation methods and delivery assessment in vivo. Through these goals, the Program will provide new preclinical candidates, along with the biology of the respective molecular targets, to investigators in other SKCCC Programs to move them further along the clinical development path. This will have a broad and powerful impact by assisting clinical researchers with basic science investigations essential to the treatment of cancer and by driving the discovery and delivery of new anticancer drugs to the clinic for real-world testing.